In cases of pancreatic insufficiency, pancrelipase and other pancreatic enzymes products (PEPs) can be administered to at least partially remedy the enzyme deficiency caused by various diseases affecting the pancreas, such as pancreatitis, pancreatectomy, cystic fibrosis, etc. The use of pancreatic enzymes in the treatment of pancreatic insufficiency is an essential part of the therapy of patients afflicted with cystic fibrosis. Without these supplements, patients become severely nutritionally impaired. This nutritional impairment can be life threatening if left untreated, particularly in the case of infants.
In addition to nutritional impairment (e.g., fat malabsorption, etc.) the majority of patients suffering from chronic pancreatitis also experience severe and often debilitating pain associated with the condition. The cause of pancreatic pain is uncertain, but has been hypothesized to be caused by pancreatic hyperstimulation as a result of the loss of feedback regulation of CCK releasing peptide. Normally, the release of pancreatic protease in response to the ingestion of a meal results in the degradation of CCK releasing peptide present in the upper GI tract, which causes a decrease in pancreatic contraction and enzyme secretion once sufficient digestive enzymes have been produced for digestion. For patients suffering from pancreatic insufficiency, the CCK releasing peptide is insufficiently degraded, thus allowing continued (hyper) stimulation of the pancreas. Although not wishing to be bound by any particular theory, according to this hypothesis for pain generation, the administration of protease enzymes (e.g. in pancreatic enzyme formulations) should degrade the CCK releasing peptide, thereby ameliorating pancreatic hyperstimulation and the resulting pancreatic pain.
Pancreatic enzymes show optimal activity under near neutral and slightly alkaline conditions. Under gastric conditions, lipase enzymes, which are often present in therapeutic enzyme compositions, are expected to become increasingly and irreversibly inactivated with decreasing pH and/or an increasing duration of exposure to low pH conditions, resulting in a loss of biological activity. Accordingly, exogenously administered enzymes are generally protected against gastric inactivation, e.g., with enteric coatings, so as to remain intact and protected from gastric acids during their transit through the stomach and into the duodenum. However, since CCK releasing peptide is secreted high in the GI tract, conventional enterically coated pancreatic enzyme preparations may not release protease enzymes sufficiently quickly or in the appropriate part of the GI tract to sufficiently degrade CCK releasing peptide and thereby reduce or eliminate pancreatic pain.
Uncoated enzyme preparations would not present the problem of slow or incomplete release in the GI tract, but would be expected to become substantially inactivated in the low pH environment of the stomach, and thus not provide sufficient levels of active digestive enzyme to treat the nutritional impairment caused by pancreatic insufficiency. One approach to treating pancreatic pain with uncoated enzyme preparations is to co-administer uncoated enzyme with proton pump inhibitors in an attempt to decrease enzyme degradation in the stomach so that some active enzyme, in particular lipase, may survive into the duodenum (Lieb et al., Aliment. Pharmacol. Ther. 29, 706-719 (2009)). Alternatively, pancreatic pain has been treated with relatively high doses of coated or uncoated pancreatic enzyme to ensure that sufficient active enzyme was delivered to the duodenum (Winstead et al., Pancreatology 9, 344-350 (2009)). For example, uncoated enzyme preparations dosed at 64,000 units of lipase, and having a nominal protease activity of 240,000 units (per meal) are suggested for the relief of pancreatic pain (Lieb et al.).
Based on a number of small clinical studies in which uncoated enzymes appeared to perform better the coated enzyme preparations used in other studies (Lieb et al.), the conventional wisdom is that coated enzyme preparations are not recommended for the treatment of pancreatic pain, while uncoated enzyme preparations may be suitable. To-date, however, there has been no controlled clinical trial that has adequately demonstrated the efficacy of pancreatic enzymes, coated or uncoated, in the treatment of pain associated with pancreatitis.
However, in order to treat both pancreatic pain (e.g. with uncoated enzyme preparations) and nutritional impairment (e.g. with coated enzyme preparations), conventional treatment methods suggest that very high doses of enzyme would be required: i.e., about 4 enterically-coated pancreatin pills, and 4 uncoated pancreatin pills per meal. This is based on the mid-point of the recommended mid-dosing of CREON 24, and expert recommendations for the dosing of uncoated enzymes (Winstead et al.), as there is presently no approved uncoated product for the treatment of pain. This places a very considerable burden on the patient and means that the total dose of enzymes that are given to a patient may give rise to safety concerns (Smyth et al. Fibrosing colonopathy in cystic fibrosis: results of a case-control study. Lancet. 1995; 346: 1247-1251; FitzSimmons et al. High-dose pancreatic-enzyme supplements and fibrosing colonopathy in children with cystic fibrosis. New England Journal of Medicine. 1997; 336: 1283-1289).
The present inventors have surprisingly found that a single dosage faun comprising the combination of a relatively lower amount of enterically coated digestive enzyme with uncoated digestive enzyme provides effective treatment of pancreatic pain and effective control of nutritional impairment, for example fat malabsorption. In addition, the present inventors have surprisingly found that a very low dose of enterically coated enzymes is effective in the treatment of malabsorption due to pancreatic insufficiency, e.g. in patients suffering from chronic pancreatitis.